US20070299088A1 - Novel Uses of 2-Phenyl-Substituted Imidazotriazinone Derivatives - Google Patents

Novel Uses of 2-Phenyl-Substituted Imidazotriazinone Derivatives Download PDF

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US20070299088A1
US20070299088A1 US11/659,624 US65962405A US2007299088A1 US 20070299088 A1 US20070299088 A1 US 20070299088A1 US 65962405 A US65962405 A US 65962405A US 2007299088 A1 US2007299088 A1 US 2007299088A1
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treatment
methyl
triazin
propyl
imidazo
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Helmut Haning
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Bayer AG
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Bayer Healthcare AG
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Definitions

  • the present invention relates to the use of PDE 5 inhibitors generally and in particular of known 2-phenyl-substituted imidazotriazinone derivatives for manufacturing medicaments for the treatment of pathological states which are treatable by raising cGMP levels in certain tissues, such as, for example, of acute myocardial infarction and reperfusion damage, of various pathological states of the female and male reproductive system and urogenital tract, of gastrointestinal disorders, diabetic damage and of renal failure.
  • cyclic nucleotide cGMP cyclic guanosine monophosphate
  • PDEs phosphodiesterases
  • PDE 5 occurs in particular in vascular smooth muscle cell tissue, and less in the kidney, lung and the blood platelets. Owing to their vasorelaxant effect, PDE 5 inhibitors are proposed for the treatment of angina and high blood pressure, but mainly for the treatment of erectile dysfunction.
  • WO 99/24433 describes 2-phenyl-substituted imidazotriazinones, their cGMP-PDE-inhibiting effect and their use for the treatment of vascular disorders, in particular for the treatment of erectile dysfunction.
  • WO 02/089808 and WO 03/011262 disclose uses of 2-phenyl-substituted imidazotriazinones.
  • Cyclic guanosine 3′,5′-monophosphate-metabolizing phosphodiesterases are PDE 1, 2, 5, 6, 9, 10 and 11.
  • the mentioned 2-phenyl-substituted imidazotriazinones used according to the invention are potent inhibitors of phosphodiesterase 5.
  • PDE 5 inhibitors preferred in this connection are those which, in the assay detailed hereinafter, inhibit PDE 5 with an IC 50 of less than 1 ⁇ M, preferably of less than 0.1 ⁇ M.
  • the PDE 5 inhibitors used according to the invention are preferably also selective in relation to cAMP PDEs, in particular in relation to PDE 4. It is particularly preferred for the inhibition of PDE 5 to be at least ten times greater.
  • One aspect of the present invention relates to the use of compounds of the general formula (I)
  • the compounds used according to the invention may, depending on their structure, exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore includes the use of the enantiomers and diastereomers and respective mixtures thereof.
  • the stereoisomerically pure constituents can be isolated from such mixtures of enantiomers and/or diastereomers in a known manner.
  • the present invention includes all tautomeric forms.
  • Salts preferred in the context of the present invention are physiologically acceptable salts of the compounds used according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used for example to isolate or purify the compounds used according to the invention.
  • Physiologically acceptable salts of the compounds used according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • mineral acids e.g. salts of mineral acids, carboxylic acids and sulfonic acids
  • Physiologically acceptable salts of the compounds used according to the invention also include salts of conventional bases such as, by way of example and preferably, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 C atoms, such as, by way of example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, prokaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • alkali metal salts e.g. sodium and potassium salts
  • alkaline earth metal salts e.g. calcium and magnesium salts
  • Solvates refer in the context of the invention to those forms of the compounds used according to the invention which form in the solid or liquid state a complex by coordination with solvent molecules. Hydrates are a specific type of solvates in which the coordination takes place with water. Hydrates are preferred as solvates in the context of the present invention. Hydrates can be prepared for example by crystallizing the relevant compound from water or a hydrous solvent.
  • the present invention also includes in addition prodrugs of the compounds used according to the invention.
  • prodrugs includes compounds which themselves may be biologically active or inactive but are converted (for example by metabolism or hydrolysis) during their residence time in the body into the compounds used according to the invention.
  • acyl radical having 1 to 3 carbon atoms is in the context of the invention for example formyl, acetyl or propionyl.
  • a straight-chain or branched alkoxy radical having 1 to 3 carbon atoms is in the context of the invention for example methoxy, ethoxy, n-propoxy or isopropoxy.
  • alkoxycarbonyl radical having 1 to 3 carbon atoms is in the context of the invention for example methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl.
  • a straight-chain or branched alkyl radical having 1 to 5 or 1 to 3 carbon atoms is in the context of the invention for example methyl, ethyl, n-propyl, isopropyl, tert-butyl or n-pentyl.
  • Straight-chain or branched alkyl radicals having 1 to 4 or 1 to 3 carbon atoms are preferred.
  • a further embodiment of the invention relates to the use according to the invention of compounds of the general formula (I) in which the radicals R 5 and —SO 2 NR 3 R 4 are positioned parallel to one another on the phenyl ring, and R 1 , R 2 , R 3 , R 4 and R 5 each have the meaning indicated above.
  • a further embodiment of the invention relates to the use according to the invention of compounds of the general formula (Ia)
  • R 1 , R 2 , R 3 , R 4 and R 5 each have the meaning indicated above,
  • a further embodiment of the invention relates to the use of the compounds of the general formulae (I) and (Ia) for manufacturing a medicament for the treatment of cardiac ischemia, for achieving or improving a preconditioning effect, for the treatment of an acute myocardial infarction and of reperfusion damage, specifically following a myocardial infarction, for the treatment of male infertility, of Raynaud's syndrome, of intermittent claudication, of Peyronie's disease, for the treatment of fibrotic disorders, of arteriosclerosis, for improving sperm motility, for the treatment of depression, leukemia (e.g.
  • liver disorders such as, for example, cirrhosis of the liver, portal hypertension for the treatment of lupus, hypertensive systemic lupus erythematosus, scleroderma, for the treatment of multiple sclerosis, rheumatoid arthritis, allergy, autoimmune diseases, osteoporosis, cachexia, polycystic ovary syndrome, inflammatory bowel diseases such as, for example, Crohn's disease and ulcerative colitis, diabetic gangrene, diabetic arthropathy, diabetic glomerulosclerosis, diabetic dermatopathy, diabetic cataract, hyperlipidemia and dyslipidemia, for promoting growth and improving survival of oocytes, zygotes, embryos or fetuses, for increasing the weight of premature babies, for increasing milk production in
  • the compounds used according to the invention may have systemic and/or local effects. They can for this purpose be administered in a suitable way, such as, for example, by the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic route or as implant or stent.
  • the compounds used according to the invention can be administered in suitable administration forms for these administration routes.
  • Administration forms suitable for oral administration are those which function according to the state of the art and deliver the compounds of the invention in a rapid and/or modified way, and which contain the compounds of the invention in crystalline and/or amorphized and/or dissolved form, such as, for example, tablets (uncoated or coated tablets, for example with coatings which are resistant to gastric juice or dissolve slowly or are insoluble and which control the release of the compound of the invention), tablets which rapidly disintegrate in the mouth, or films/wafers, films/lyophilisates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • tablets uncoated or coated tablets, for example with coatings which are resistant to gastric juice or dissolve slowly or are insoluble and which control the release of the compound of the invention
  • tablets which rapidly disintegrate in the mouth or films/wafers, films/lyophilisates
  • capsules for example hard or soft gelatin capsules
  • Parenteral administration can take place with avoidance of an absorption step (e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with inclusion of an absorption (e.g. intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • Administration forms suitable for parenteral administration are, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Examples suitable for other administration routes are medicinal forms for inhalation (inter alia powder inhalators, nebulizers), nasal drops in solutions or sprays; tablets for lingual, sublingual or buccal administration, films/wafers or capsules, suppositories, preparations for the ears or eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
  • inhalation inter alia powder inhalators, nebulizers
  • nasal drops in solutions or sprays tablets for lingual, sublingual or buccal administration, films/wafers or capsules, suppositories, preparations for the ears or eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as, for example
  • Oral or parenteral administration are preferred, especially oral and intravenous administration.
  • Intravenous dosage is particularly preferred for example for the treatment of acute myocardial infarction and of reperfusion damage; incremental intravenous dosage is also possible here.
  • the compounds used according to the invention can be converted into the stated administration forms. This can take place in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients include, inter alia, carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants such as, for example, ascorbic acid), colors (e.g. inorganic pigments such as, for example, iron oxides) and masking tastes and/or odors.
  • carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents e.g. liquid polyethylene glycols
  • the present invention further relates to medicaments which comprise at least one compound used according to the invention, normally together with one or more inert, non-toxic, pharmaceutically suitable excipients, and to the use thereof for the aforementioned purposes.
  • parenteral administration it has generally proved advantageous on parenteral administration to administer amounts of about 0.001 to 10 mg/kg, preferably about 0.01 to 1 mg/kg, of body weight to achieve effective results.
  • the amount on oral administration is about 0.01 to 100 mg/kg, preferably about 0.1 to 30 mg/kg, and very particularly preferably 0.1 to 10 mg/kg, of body weight.
  • Exemplary embodiment 1 is 2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one; this compound is prepared in accordance with example 16 in WO 99/24433.
  • Exemplary embodiment 2 is 2-[2-ethoxy-5-(4-ethylpiperazine-1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazol[5,1-f][1,2,4]triazin-4-one hydrochloride trihydrate; this compound is prepared in accordance with example 336 in WO 99/24433.
  • the PDE- and PDE 5-inhibiting effect of the compounds used according to the invention can be determined as follows:
  • the inhibitory effect is assayed by using the phosphodiesterase [ 3 H] cGMP-SPA enzyme assay supplied by Amersham Life Science.
  • the assay is carried out in accordance with the experimental protocol indicated by the manufacturer.
  • Human recombinant PDE 5 which has been expressed in a bacculovirus system is used.
  • the substance concentration at which the reaction rate is reduced by 50% is measured.
  • Exemplary embodiments 1 and 2 show IC 50 values respectively of 0.6 and 0.7 nM in this assay.
  • PDE1C GenBank/EMBL Accession Number: NM — 005020, Loughney et al. J. Biol. Chem. 1996, 271, 796-806
  • PDE2A GenBank/EMBL Accession Number: NM — 002599, Rosman et al. Gene 1997, 191, 89-95
  • PDE3B GenBank/EMBL Accession Number: NM — 000922, Miki et al. Genomics 1996, 36, 476-485
  • PDE4B GenBank/EMBL Accession Number: NM — 002600, Obernolte et al. Gene.
  • PDE5A GenBank/EMBL Accession Number: NM — 001083, Loughney et al. Gene 1998, 216, 139-147
  • PDE7B GenBank/EMBL Accession Number: NM — 018945, Hetman et al. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 472-476
  • PDE8A GenBank/EMBL Accession Number: AF — 056490, Fisher et al. Biochem. Biophys. Res. Commun. 1998, 246, 570-577
  • PDE9A Fisher et al., J. Biol.
  • test substances are dissolved in 100% DMSO and serially diluted to determine their in vitro effect on PDE9A.
  • serial dilutions from 200 ⁇ M to 1.6 ⁇ M are prepared (resulting final concentrations in the assay: 4 ⁇ M to 0.032 ⁇ M).
  • 2 ⁇ L portions of the diluted substance solutions are introduced into the wells of microtiter plates (Isoplate; Wallac Inc., Atlanta, Ga.). Then 50 ⁇ L of a dilution of the PDE9A preparation described above are added.
  • the dilution of the PDE9A preparation is chosen so that less than 70% of the substrate is converted during the subsequent incubation (typical dilution: 1:10 000; dilution buffer: 50 mM Tris/HCl pH 7.5, 8.3 mM MgCl 2 , 1.7 mM EDTA, 0.2% BSA).
  • the substrate [8- 3 H]guanosine 3′,5′-cyclic phosphate (1 ⁇ Ci/ ⁇ L; Amersham Pharmacia Biotech., Piscataway, N.J.) is diluted 1:2000 with assay buffer (50 mM Tris/HCl pH 7.5, 8.3 mM MgCl 2 , 1.7 mM EDTA) to a concentration of 0.0005 ⁇ Ci/ ⁇ L.
  • the enzyme reaction is finally started by adding 50 ⁇ L (0.025 ⁇ Ci) of the diluted substrate.
  • the assay mixtures are incubated at room temperature for 60 min and the reaction is stopped by adding 25 ⁇ l of a PDE9A inhibitor (e.g.
  • the protocol is additionally adapted as follows: with PDE1C, additionally 10 ⁇ 7 M calmodulin and 3 mM CaCl 2 are added to the reaction mixture. PDE2A is stimulated in the assay by adding 1 ⁇ M cGMP and is assayed with a BSA concentration of 0.01%.
  • the substrate employed for PDE1C and PDE2A is [5′,8- 3 H]adenosine 3′,5′-cyclic phosphate (1 ⁇ Ci/ ⁇ L; Amersham Pharmacia Biotech., Piscataway, N.J.), and for PDE5A is [8- 3 H]guanosine 3′,5′-cyclic phosphate (1 ⁇ Ci/ ⁇ L; Amersham Pharmacia Biotech., Piscataway, N.J.).

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ES2548759T3 (es) 2006-08-24 2015-10-20 Surface Logix, Inc. Compuestos farmacocinéticamente mejorados
WO2010042682A1 (en) * 2008-10-08 2010-04-15 Bristol-Myers Squibb Company Azolotriazinone melanin concentrating hormone receptor-1 antagonists
UA116521C2 (uk) * 2010-05-26 2018-04-10 Адверіо Фарма Гмбх Застосування sgc-стимуляторів, sgc-активаторів окремо і в комбінації з інгібіторами фде5 для лікування системної склеродермії (ssc)
CN103391941A (zh) * 2011-02-23 2013-11-13 辉瑞大药厂 用于治疗神经障碍的咪唑并[5,1-f][1,2,4]三嗪类
RU2497203C2 (ru) * 2012-02-13 2013-10-27 Государственное бюджетное образовательное учреждение высшего профессионального образования "Курский государственный медицинский университет" Министерства здравоохранения и социального развития Российской Федерации Способ фармакологической коррекции ишемии скелетной мышцы силденафилом, в том числе при l-name-индуцированном дефиците оксида азота

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